Producing Z-isomer of hydrogen bromide salt of 2-aminothiazole derivative

ABSTRACT

There is disclosed a process for producing an acid salt of a (Z)-2-aminothiazole compound of the formula (I):wherein R1 and R2 independently represent an alkyl group having 1 to 5 carbon atoms, Y represents a halogen atom, -OSO3H or -OPO(OH)2,m indicates the valence number of an inorganic acid of the formula:HY wherein Y represents the same as defined above, andn indicates an integer of 1 or 2,which process is characterized by:reacting an acid salt of a 2-aminothiazole compound of the formula (II):wherein R1 and R2 independently represent an alkyl group having 1 to 5 carbon atoms, X represents a bromine atom or an iodine atom, and the wavy line means that this compound is a mixture of the E- and Z-isomers, with the inorganic acid of the formula HY.

FIELD OF THE INVENTION

The present invention relates to a process for producing a hydrogenbromide salt of a (Z)-2-aminothiazole derivative which is useful as anintermediate of pharmaceuticals, for example, an intermediate forconstructing a side chain part of the antibiotics disclosed inEP467647B1, which corresponds to Japanese Patent No. 2618119.

DESCRIPTION OF THE RELATED ART

A process for producing a hydrogen bromide salt of the(Z)-2-aminothiazole derivative is disclosed in Preparation 6 ofEP467647B1, however, the process is not always satisfactory as anindustrial production method in that no reproducible particulars on howto control the exothermic reaction is disclosed. Hence an improvedprocess has been desired.

SUMMARY OF THE INVENTION

An object of the invention is to provide a method for producing an acidsalt of a (Z)-2-aminothiazole derivative of the formula I as depictedbelow.

Another object of the invention is to provide an industriallyadvantageous reaction method, particularly a continuous method, forpreferentially producing a Z-isomer of a hydrogen bromide salt of a2-aminothiazole derivative of the formula (I), while effectivelycontrolling the exothermic reaction on an industrial scale production.

The present invention provides:

1. a process for producing an acid salt of a (Z)-2-aminothiazolecompound of the formula (I):

wherein

R¹ and R² independently represent an alkyl group having 1 to 5 carbonatoms,

Y represents a halogen atom, —OSO₃H or —OPO(OH)₂,

m indicates the valence number of an inorganic acid of HY and

n indicates an integer of 1 or 2,

which process comprises:

reacting an acid salt of a 2-aminothiazole compound of the formula (II):

wherein R¹ and R² independently represent an alkyl group having 1 to 5carbon atoms, the wavy line means that this compound is a mixture of theE- and Z-isomers, and X represents a bromine atom or an iodine atom,with an inorganic acid of the formula (III):

HY  (III)

wherein Y represents a halogen atom, —OSO₃H or —OPO(OH)₂.

2. a continuous process for preferentially producing a Z-isomer of ahydrogen bromide salt of a 2-aminothiazole derivative of the formula(IV):

wherein

R¹ and R² independently represent a lower alkyl group having 1 to 5carbon atoms, and the wavy line means that this compound is a mixture ofthe E- and Z-isomers,

which process comprises:

continuously feeding thiourea and a 2-alkylidene-4-bromoacetoacetic acidester of the formula (V):

wherein R¹ and R² have the same meaning as defined above, and the wavyline means that this compound is a mixture of the E- and Z-isomers, intoa reaction vessel having at least one agitator,

reacting the thiourea and the compound of the formula (V) together inthe reaction vessel for a sufficient residence time for the conversionof the compound of the formula (V) to the compound of the formula (IV),and

withdrawing a resulting reaction mixture containing the compound of theformula (IV) from the reaction vessel as an effluent; and

3. a process for preferentially producing a Z-isomer of a hydrogenbromide salt of a 2-aminothiazole derivative of the formula (IV) asdefined above,

which process comprises:

reacting thiourea and a 2-alkylidene-4-bromoacetoacetic ester of theformula (V) as defined above, wherein the reaction temperature of thereaction is maintained at a temperature of −10 to +45° C. and thereaction time Rt of the reaction is defined by the following inequality:

60e ^((−0.15T)) ≦Rt≦180e ^((−0.17T)),

wherein “T” means a reaction temperature.

In the present invention the term “Rt” stands for both “Reaction Time”(when reference a batch reaction in a reaction vessel), and “ResidenceTime” (when reference continuous reaction in a reaction vessel).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

First, a description will be made to the first aspect of the presentinvention drawn to the process for producing an acid salt of a(Z)-2-aminothiazole compound of the formula (I), which process comprisesreacting an acid salt of a 2-aminothiazole compound of the formula (II)with an inorganic acid of the formula (III).

Examples of the lower alkyl group having 1 to 5 carbon atoms for R¹ andR² of the formulae (I), (II) and (VI) each independently include amethyl group, an ethyl group, an n-propyl group, an isopropyl group, ann-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, an-pentyl group and a neopentyl group.

Examples of the lower alkyl group having 1 to 5 carbon atoms for R¹ andR² of the formulae (IV) and (V) described for the second aspect of thepresent invention also include the same as described above.

The group Y in the acid salt of the (Z)-2-aminothiazole compound of theformulae (I) and (III) represents a halogen atom such as chlorine,bromine and the like, or represents —OSO₃H or —OPO(OH)₂.

The X in the acid salt of the 2-aminothiazole compound of the formula(II) represents a bromine atom or an iodine atom.

Examples of the acid salt of the 2-aminothiazole compound of the formula(II) include hydrogen bromide salts or hydrogen iodide salts of thefollowing compounds:

methyl 2-(2-aminothiazole-4-yl)-2-butenoate,

ethyl 2-(2-aminothiazole-4-yl)-2-butenoate,

n-propyl 2-(2-aminothiazole-4-yl)-2-butenoate,

isopropyl 2-(2-aminothiazole-4-yl)-2-butenoate,

n-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,

t-butyl 2-(2-aminothiazole-4-yl)-2-butenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-2-butenoate,

methyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

ethyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

n-propyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

isopropyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

n-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

t-butyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-2-pentenoate,

methyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

ethyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

n-propyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

isopropyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

n-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

t-butyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-2-hexenoate,

methyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

ethyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

n-propyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

isopropyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

n-butyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

t-butyl 2-(2-aminothiazole-4yl)-4-methyl-2-pentenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

methyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

ethyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

n-propyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

isopropyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

n-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

t-butyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-2-heptenoate,

methyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

ethyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

n-propyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

isopropyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

n-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

t-butyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

n-pentyl 2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

methyl 2-(2-aminothiazole-4-yl)-2-octenoate,

ethyl 2-(2-aminothiazole-4-yl)-2-octenoate,

n-propyl 2-(2-aminothiazole-4-yl)-2-octenoate,

isopropyl 2-(2-aminothiazole-4-yl)-2-octenoate,

n-butyl 2-(2-aminothiazole-4-yl)-2-octenoate,

t-butyl 2-(2-aminothiazole-4-yl)-2-octenoate and

n-pentyl 2-(2-aminothiazole-4-yl)-2-octenoate, and mixtures of two ormore of these acid salts.

Z-isomer rich hydrogen bromide salts of the above-described2-aminothiazole derivative are preferably used in the present processand can be obtained by a known method or by the methods of the presentinvention described below.

Examples of the inorganic acid of the formula (III) include hydrogenhalide such as hydrogen chloride and hydrogen bromide, sulfuric acid,phosphoric acid, and the like. Preferred are hydrogen chloride andhydrogen bromide, and hydrogen chloride is used more preferably.Although the inorganic acid is usually used singly, mixtures of two ormore inorganic acids can be used. The amount of the inorganic acid to beused is 0.3 to 10 moles, preferably 0.5 to 5 moles per mole of the acidsalt of the 2-aminothiazole compound (II).

Although an anhydrous inorganic acid such as a gaseous inorganic acidcan be used, an aqueous solution of the inorganic acid is usually used.The concentration of the aqueous acid solution is usually 2 to 99%,preferably 4 to 70%.

Alternatively, a solution of the anhydrous inorganic acid (III) absorbedin an organic solvent also can be employed. Examples of the organicsolvent include:

aromatic hydrocarbons such as benzene, toluene and xylene;

aliphatic hydrocarbons such as hexane and heptane;

halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane,chloroform, 1-chlorobutane and chlorobenzene,

ethers such as diethyl ether, t-butyl methyl ether, tetrahydrofuran,1,2-dimethoxyethane, diglyme and triglyme;

ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone;

amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone;

alcohols such as methanol, ethanol, 1-propanol, 2-propanol and1-butanol; and

nitrites such as acetonitrile. Such organic solvents may be used eithersingly or in mixtures of two or more of them.

The amount of the organic solvent to be used is usually 0.2 to 50 parts,preferably 0.5 to 20 parts per 1 part by weight of the inorganic acid(III).

The reaction between the acid salt of the 2-aminothiazole compound ofthe formula (II) and the inorganic acid of the formula (III) is usuallycarried out in the presence of a solvent. Examples of the solventinclude those as exemplified above for absorbing gaseous inorganic acidas well as water.

Such solvents are used singly or in combinations of two or more of them.Preferably, a water miscible organic solvent is used.

Examples of such a water miscible organic solvent include:

ethers such as 1,2-dimethoxyethane, diglyme and triglyme;

ketones such as acetone and methyl ethyl ketone;

amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone;

alcohols such as methanol, ethanol and 2-propanol;

nitrites such as acetonitrile.

The amount of the organic solvent or water to be used is usually 0.5 to100 parts, preferably 1 to 50 parts per 1 part by weight of the acidsalt of the 2-aminothiazole compound (II).

The reaction of the acid salt of the 2-aminothiazole compound (II) withthe inorganic acid (III) is carried out, for example, by adding anaqueous solution of the inorganic acid (III) to a solution containingthe acid salt of the 2-aminothiazole compound (II). Alternatively, thesolution containing the acid salt of the 2-aminothiazole compound (II)may be added to the aqueous solution of the inorganic acid (III).

The reaction is carried out at temperatures not less than thesolidifying point of the reaction mixture. The reaction temperature isusually −40 to 40° C., preferably −20 to 20° C.

The reaction time is not particularly limited, and usually is about 0.5to 48 hours.

The acid salt of the (Z)-2-aminothiazole compound of the formula (I)obtained may be added as a seed crystal before or during mixing the acidsalt of the 2-aminothiazole compound (II) and the inorganic acid (III),if necessary. Such an addition of the seed crystal may result in smoothprecipitation of crystals from the reaction mixture.

After completion of the reaction, the acid salt of the(Z)-2-aminothiazole compound of the formula (I) can be isolated ascrystals by filtering the precipitates from the reaction mixture.

The crystals of the acid salt of the (Z)-2-aminothiazole compound (I)thus obtained may be washed with a solvent, if necessary. Examples ofthe solvent that can be used for washing the crystals include thosedescribed above for the reaction of the acid salt of the 2-aminothiazolecompound (II) with the inorganic acid (III). Such solvents are usedsingly or in combination of two or more of them.

The amount of the solvent used is usually 0.1 to 20 parts, preferably0.3 to 10 parts by 1 part by weight of the acid salt (II) of the2-aminothiazole compound.

The crystals are washed usually at −40 to 40° C., preferably −20 to 20°C.

Thus obtained crystals of the acid salt of the (Z)-2-aminothiazolecompound of the formula (I) can be dried in a conventional manner.Alternatively, crystals containing the organic solvents used in thereaction and/or washing can be used with no problem without being dried.

When a solvent containing water is used as a solvent in the reactionand/or washing, the acid salt of the (Z)-2-aminothiazole compound of theformula (I) obtained may contain crystal water. Even in such a case, theacid salt of the (Z)-2-aminothiazole compound (I) can be produced andused with no problem.

Thus the acid salt of the (Z)-2-aminothiazole compound of the formula(I) can be obtained. Examples of the acid salt of the(Z)-2-aminothiazole compound (I) include:

hydrochlorides, hydrobromides, hydriodides, dihydrochlorides,dihydrobromides, dihydriodides, hydrogen sulfates and 1/3-phosphates ofthe following compounds:

methyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-butenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-hexenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl-4-methyl-2-pentenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

n-butyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-4-methyl-2-pentenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

n-butyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-heptenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl-4,4-dimethyl-2-pentenoate

n-butyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-4,4-dimethyl-2-pentenoate,

methyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,

ethyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,

n-propyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,

isopropyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate,

n-butyl (Z)-2-(2-aminothiazole-4yl)-2-octenoate,

t-butyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate and

n-pentyl (Z)-2-(2-aminothiazole-4-yl)-2-octenoate.

When the substituent X in the acid salt of the 2-aminothiazole compoundof the formula (II) is not the same as the group Y in the inorganic acidof the formula (III), the acid salt of a (Z)-2-aminothiazole compound ofthe formula (I) may be obtained as a mixed acid salt of the(Z)-2-aminothiazole compound of the formula (I) as described above.

The acid salt of the (Z)-2-aminothiazole compound of the formula (I)can, for example, be converted to a free (Z)-2-aminothiazole compound byallowing it to react with a base such as sodium hydrogencarbonate, ifnecessary.

The acid salt of the (Z)-2-aminothiazole compound (I) as described abovecan be manufactured and used with encountering no problem.

The acid salt of the 2-aminothiazole compound of the formula (II) thatis used in the above-described process, can be prepared, for example, byreacting a halogenated compound of the formula (VI):

wherein

R¹ and R² independently represent an alkyl group having 1 to 5 carbonatoms,

X represents a bromine atom or an iodine atom and the wavy line meansthat this compound is a mixture of the E- and Z-isomers, with thioureaunder similar conditions as described below, but manufacturingconditions or methods of the salt are not particularly limited thereto.

Next, a description will be made to the second aspect of the presentinvention regarding the continuous process for preferentially producingthe compound of the formula (IV) from a 2-alkylidene-4-bromoacetoaceticacid ester of the formula (V).

Although the 2-alkylidene-4-bromoacetoacetic ester of the formula (VI)to be used in the second aspect of the present invention can beobtained, for example, according to the method disclosed in the EP0467647B1, the production method of the compound is not restricted tothe disclosed process.

Specific examples of the 2-alkylidene-4-bromoacetoacetic ester of theformula (VI) include:

methyl 2-ethylidene-4-bromoacetoacetate,

ethyl 2-ethylidene-4-bromoacetoacetate,

n-propyl 2-ethylidene-4-bromoacetoacetate,

i-propyl 2-ethylidene-4-bromoacetoacetate,

n-butyl 2-ethylidene-4-bromoacetoacetate,

t-butyl 2-ethylidene-4-bromoacetoacetate,

n-pentyl 2-ethylidene-4-bromoacetoacetate,

methyl 2-propylidene-4-bromoacetoacetate,

ethyl 2-propylidene-4-bromoacetoacetate,

n-propyl 2-propylidene-4-bromoacetoacetate,

i-propyl 2-propylidene-4-bromoacetoacetate,

n-butyl 2-propylidene-4-bromoacetoacetate,

t-butyl 2-propylidene-4-bromoacetoacetate,

n-pentyl 2-propylidene-4-bromoacetoacetate,

methyl 2-butylidene-4-bromoacetoacetate,

ethyl 2-butylidene-4-bromoacetoacetate,

n-propyl 2-butylidene-4-bromoacetoacetate,

i-propyl 2-butylidene-4-bromoacetoacetate,

n-butyl 2-butylidene-4-bromoacetoacetate,

t-butyl 2-butylidene-4-bromoacetoacetate,

n-pentyl 2-butylidene-4-bromoacetoacetate,

methyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

ethyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

n-propyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

i-propyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

n-butyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

t-butyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

n-pentyl 2-(2-methylpropylidene)-4-bromoacetoacetate,

methyl 2-pentylidene-4-bromoacetoacetate,

ethyl 2-pentylidene-4-bromoacetoacetate,

n-propyl 2-pentylidene-4-bromoacetoacetate,

i-propyl 2-pentylidene-4-bromoacetoacetate,

n-butyl 2-pentylidene-4-bromoacetoacetate,

t-butyl 2-pentylidene-4-bromoacetoacetate,

n-pentyl 2-pentylidene-4-bromoacetoacetate,

methyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

ethyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

n-propyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

i-propyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

n-butyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

t-butyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

n-pentyl 2-(2,2-dimethylpropylidene)-4-bromoacetoacetate,

methyl 2-hexylidene-4-bromoacetoacetate,

ethyl 2-hexylidene-4-bromoacetoacetate,

n-propyl 2-hexylidene-4-bromoacetoacetate,

i-propyl 2-hexylidene-4-bromoacetoacetate,

n-butyl 2-hexylidene-4-bromoacetoacetate,

t-butyl 2-hexylidene-4-bromoacetoacetate,

n-pentyl 2-hexylidene-4-bromoacetoacetate, and the like.

The amount of thiourea to be used is usually from 0.5 to 10 moles,preferably from 0.9 to 5 moles per mol of the2-alkylidene-4-bromoacetoacetic ester of the formula (VI).

In the continuous process of the present invention, the reaction ispreferably conducted so that the resulting mixture is preferablymaintained at a predetermined temperature (e.g., −10 to +45° C.) so thatundesirable side reactions are reduced, and the reactor is designed tohave sufficient residence time for the conversion of the fed reactants.

The solution of the 2-alkylidene-4-bromoacetoacetic acid ester and asolution of thiourea are usually continuously charged by a pump such asa gear pump, syringe pump and the like into the reaction vessel.

The reaction vessel usually contains a transfer line connected ahead toa tubular reactor which may be further connected with a transfer tubularline. The solutions of the reactants (thiourea and the compound of theformula (V)) are usually continuously fed into the transfer lineconnected ahead to a tubular reactor or directly into the reactor inwhich the reactants are thoroughly mixed by an agitator equippedthereto, and further conversion of the reactants is allowed in thefollowing transfer tubular line, if necessary.

Examples of the reaction vessel to be used in the present inventioninclude a tubular reactor having at least one agitator arranged singlyor in series which can cause a sufficient turbulent flow to the chargedreactant solutions.

Examples of the agitator include:

a static mixer, wherein variously shaped vanes causing a turbulent flowof the reactant solutions are placed in a tubular casing,

an agitator wherein a vane placed in a tubular casing is rotated so asto make a turbulent flow as described above,

an agitator having a vane fixed to the inner wall of a tubular casingand a stirrer fixed to a shaft that is mounted in the tubular casing andreciprocates in the axis direction, and

an agitator having a helical vane fixed to a shaft which is set in thetubular casing and the shaft is connected to a vibration source, whereinthe helical vane and the tubular casing form a helical passage for thereactant solution.

Among these, preferably employed are:

a static mixer (e.g., Noritake Static Mixer manufactured by NoritakeCompany, Limited, TK-ROSS LPD Mixer and Motionless Mixer manufactured byTokusyukika-kogyou, Ltd, Sulzer Mixer manufacture by Sumitomo HeavyIndustries, Ltd, Myu Mixer manufactured by Iken Kogyou, Ltd, SquareMixer manufacture by Sakura Seisakusyo, Ltd, Satake Multiline Mixermanufactured by Satake Kagaku Kikai Kogyou, Ltd and Pipeline Agitatormanufacture by Shimazaki Seisakusyo, Ltd.),

an agitator having a helical vane fixed to a shaft which is set in thetubular casing and the shaft is connected to a vibration source or to acrankshaft of a motor, thereby forming a helical passage for thereactant solutions as disclosed in JP 4-235729 A and Journal ofFermentation and Bioengineering Vol. 78, No.4.pp293-297, 1994, the wholedisclosures of which are incorporated herein by reference.

The tubular reactor of the present invention may be further partitionedwith a plurality of perforated partition plates which are set in thetubular line to mix the reactant solution flow in a plurality of stages.

A mixed reaction solution obtained by feeding and mixing a solution ofthe 2-alkylidene-4-bromoacetoacetic ester and a solution of thiourea ina tubular reactor may thereafter be passed through an ordinary tubularline, i.e., pipe to be retained for a desired residence time (reactiontime).

The reactants of the formula (V) and thiouera are usually fed into thereactor as a solution in a solvent. Examples of the solvent to be usedinclude those organic solvents used in the first aspect of the presentinvention. The solvents may be used singly or in combination of two ormore of them. The amount of the solvent used is not particularly limitedand is usually from 0.5 to 100 parts, preferably from 1 to 30 parts per1 part by weight of the 2-alkylidene-4-bromoacetoacetic ester of theformula (V).

The amount of the solvent to be used for dissolving thiourea is such anamount that does not allow to precipitate the thiourea at a reactiontemperature described below. Preferably used are amide solvent asdescribed above to dissolve the thiourea.

The reaction is preferably conducted at a temperature of from −10 to 45°C. so that the highest sustainably controlled temperature of thereaction is maintained at a temperature of from −10 to 45° C. Even morepreferably the reaction is conducted at a temperature of from 0 to 35°C. so that the highest sustainably controlled temperature is maintainedat a temperature of from 0 to 35° C.

The resulting reaction mixture is usually withdrawn from the reactionvessel as an effluent, which is, for example, then immediately cooled toreduce undesirable side reactions, such as the isomerization reaction ofthe desired hydrogen bromide salt of the (Z)-2-aminothiazole derivativeto its E-isomer. The reaction mixture is for example, cooled usually to0° C. or less, preferably to −10° C. or less, and more preferably to−30° C. or less to effectively suppress isomerization reaction.Alternatively, the withdrawn reaction mixture may be added dropwise toan aqueous acidic solution as used in the first aspect of the presentinvention.

Therefore, residence time (reaction time) Rt is preferably set at arange defined by the following inequality:

 60e ^((−0.15T)) ≦Rt≦180e ^((−0.1T)),

wherein “T” is the highest sustainably controlled temperature.

The method of cooling may be, but is not restricted to, being carriedout by cooling the reaction mixture obtained indirectly using arefrigerant, or by directly pouring the reaction mixture into a solventpreviously cooled such as 1-chlrobutane and the like, or by adding acooled material such as a solvent previously cooled and/or dry ice tothe effluent reaction mixture, and the like.

Alternatively, the reaction can be carried out by mixing a solution ofthe 2-alkylidene-4-bromoacetoacetic ester of the formula (IV) and asolution of thiourea quickly under similar reaction conditions asdescribed above taking account of the exothermic amount of the reactionbut in a single stage reaction within the above-described preferablereaction temperature and time.

The process of the present invention can preferentially produce theZ-isomer of the hydrogen bromide salt of the 2-aminothiazole derivative,which is useful as an intermediate to pharmaceuticals and can be furtherpurified advantageously as a desired Z-isomer by the present method asdescribed above.

EXAMPLES

The present invention will be explained in detail, but are not to beconstrued to limit the scope of the invention thereto.

Production Example 1 of methyl 2-propylidene-4-bromoacetoacetate

Into a solution obtained by dissolving 35.6 g (593 mmol) of acetic acidin 369 g of 1-chlorobutane, three components, including 253.5 g (1300mmol) of methyl 4-bromoacetoacetate, 172.2 g (2964 mmol) ofpropionaldehyde and 12.6 g (148 mmol) of piperidine, were addedseparately in parallel over a period of 6 hours at −25 to −30° C. Afterbeing held at that temperature for 2 hours, the reaction mixture waspoured into 378 g of a 1.4% aqueous hydrochloric acid. The mixture washeated to 5° C. and separated into an aqueous and organic layer. Theorganic layer was washed with 426 g of an aqueous sodium hydrogensulfitesolution (40.7 g in terms of sulfurous acid gas) at 0 to 5° C., and theoil layer separated was further washed with 363 g of water to give 732 gof a solution containing 267 g (1135 mmol, 87% yield) of methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane.

Example 1

To 18.7 g of the solution containing methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained inProduction Example 1, which solution contains (6.79 g, 28.9 mmol of puremethyl 2-propylidene-4-bromoacetoacetate), 9.8 g of 1-chlorobutane and9.8 g of acetone were added, and the mixture was cooled to −30° C. Tothe resulting solution, a solution obtained by dissolving 2.49 g (32.8mmol) of thiourea in 10.3 g of N,N-dimethylformamide was poured quicklyand stirred at 20° C. for 5 minutes. The mixture was poured into 9.1 gof 1-chlorobutane which had been cooled to −10° C. to give 60.2 g of asolution containing 5.08 g (17.3 mmol, 59.9% yield) of a hydrogenbromide salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and2.40 g (8.2 mmol, 28.4% yield) of a hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate. (The E/Z ratio was 32/68.)

Examples 2 to 12

The results shown in Table 1 were obtained by carrying out the reactionin the same manner as Example 1 except that the reaction temperature andthe reaction time were set to the values provided in Table 1.

TABLE 1 Reaction Reaction time Z-isomer temperature (° C.) (minute)yield (%) E/Z ratio Example 2 20 10 57.9 33/67 Example 3 20 15 57.034/66 Example 4 20 20 56.0 35/65 Example 5 25 5 58.9 33/67 Example 6 257.5 58.3 33/67 Example 7 25 10 58.2 34/66 Example 8 30 3.5 57.7 33/67Example 9 30 5 57.5 34/66 Example 10 30 7.5 56.5 35/65 Example 11 35 256.4 34/66 Example 12 35 5 55.5 36/64

Example 13

To 60.2 g of the solution obtained in Example 1 containing 5.08 g (17.3mmol) of the hydrogen bromide salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and 2.40 g (8.2 mmol) of thehydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate, 6.9 g of water was added at−15 to −10° C. and the mixture was separated into an aqueous and organiclayer. To the aqueous layer was added dropwise 5.4 g (53.6 mmol) of a36% hydrochloric acid at −10 to −5° C. over a period of 30 minutes.After being held at that temperature for 2 hours, the reaction mixturewas filtered at the same temperature to give crystals. The crystalsobtained were washed with two portions of 10.5 g of acetone which hadbeen cooled to −10 to −5° C., and were dried under reduced pressure toafford 3.64 g of crystals containing an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.26 g (13.1 mmol) in terms of hydrochloride. (The yieldwas 45.3% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.01 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.4/99.6.

Examples 14 to 24

The results shown in Table 2 were obtained by carrying out the reactionin the same manner as Example 13 except for using the reaction solutionsobtained in Examples 2 to 12 instead of the after reaction solutionobtained in Example 1.

TABLE 2 Example No. Z-isomer yield (%) E/Z ratio Example 14 45.50.4/99.6 Example 15 44.8 0.4/99.6 Example 16 43.8 0.6/99.5 Example 1746.2 0.4/99.6 Example 18 46.7 0.3/99.7 Example 19 46.9 0.3/99.7 Example20 45.7 0.2/99.8 Example 21 46.3 0.4/99.6 Example 22 44.9 0.2/99.8Example 23 45.3 0.3/99.7 Example 24 43.9 0.3/99.7

Example 25

Into a flask (capacity: 22 ml), provided with a bypass for taking out acontent therethrough from the side wall of the flask, were added inparallel a solution prepared by mixing a solution of methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained in the samemanner as Production Example 1 (pure methyl2-propylidene-4-bromoacetoacetate content: 31.9% by weight) with 1.4parts by weight (relative to pure methyl2-propylidene-4-bromoacetoacetate) of 1-chlorobutane and 1.4 parts byweight (relative to pure methyl 2-propylidene-4-bromoacetoacetate) ofacetone at a rate of 3.23 g/min and a solution prepared by dissolvingthiourea in N,N-dimethylformamide (thiourea content: 19.5% by weight) ata rate of 1.00 g/min. The mixed reaction solution was held at 25° C. andthe average residence time was 5 minutes. While the two solutions werestirred and mixed, the mixed reaction solution obtained was taken outthrough the bypass and poured into 1-chlorobutane which had been cooledto −30° C. previously to give a hydrogen bromide salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate with a yield of 48.4%. Theyield of a hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate was 23.8%. (The E/Z ratio was33/67.)

Example 26

Into a flask (capacity: 22 ml), provided with a bypass for taking out acontent therethrough from the side wall of the flask, were added inparallel a solution prepared by mixing a solution of methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained in the samemanner as Production Example 1 (pure methyl2-propylidene-4-bromoacetoacetate content: 31.9% by weight) with 1.4parts by weight (relative to pure methyl2-propylidene-4-bromoacetoacetate) of 1-chlorobutane and 1.4 parts byweight (relative to pure methyl 2-propylidene-4-bromoacetoacetate) ofacetone at a rate of 1.61 g/min and a solution prepared by dissolvingthiourea in N,N-dimethylformamide (thiourea content: 19.5% by weight)with a rate of 0.51 g/min. The mixed reaction solution was held at 25°C. and the average residence time was 10 minutes. While the twosolutions were stirred and mixed, the mixed reaction solution obtainedwas taken out through the bypass and poured into 1-chlorobutane whichhad been cooled to −30° C. previously to give a hydrogen bromide salt ofmethyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate with a yield of 45.9%.The yield of a hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate was 28.4%. (The E/Z ratio was36/64.)

Example 27

Into a pipe (capacity: 1116 ml) connected to a VIBRO MIXER® (capacity:192 ml) manufactured by Reika Kogyo Co. were added dropwise in parallela solution prepared by mixing a solution of methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained in the samemanner as Production Example 1 (pure methyl2-propylidene-4-bromoacetoacetate content: 32.3% by weight) with 1.56parts by weight (relative to pure methyl2-propylidene-4-bromoacetoacetate) of 1-chlorobutane and 1.56 parts byweight (relative to pure methyl 2-propylidene-4-bromoacetoacetate) ofacetone at a rate of 97.8 g/min and a solution prepared by dissolvingthiourea in N,N-dimethylformamide (thiourea content: 19.8% by weight) ata rate of 29.6 g/min. The mixed reaction solution was held at 25° C. andthe average residence time was 10 minutes. While the two solutions werestirred and mixed, the mixed reaction solution obtained was taken outthrough the outlet of the pipe and poured into 1-chlorobutane which hadbeen cooled to −18 to −15° C. previously to give a hydrogen bromide saltof methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate with a yield of58.7%. The yield of a hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate was 29.5%. (The E/Z ratio was33/67.)

Example 28

Into a tubular reactor having a static mixer (capacity: 3.9 ml, numberof element to cause turbulance to the flow: 24) to which is connected apipe (capacity: 4164 ml) were charged in parallel a solution prepared bymixing a solution of methyl 2-propylidene-4-bromoacetoacetate in1-chlorobutane obtained in the same manner as Production Example 1 (puremethyl 2-propylidene-4-bromoacetoacetate content: 33.4% by weight) with1.4 parts by weight (relative to pure methyl2-propylidene-4-bromoacetoacetate) of 1-chlorobutane and 1.4 parts byweight (relative to pure methyl 2-propylidene-4-bromoacetoacetate) ofacetone at a rate of 297.5 g/min and a solution prepared by dissolvingthiourea in N,N-dimethylformamide (thiourea content: 19.5% by weight) ata rate of 87.9 g/min, while the reaction mixture was maintained at 25°C. and the average residence time was maintained 10 minutes. The mixedreaction solution obtained was taken out through the outlet of the pipeand poured into 1-chlorobutane which had been cooled to −20 to −15° C.previously to give a hydrogen bromide salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate in a yield of 63.5%. The yieldof a hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate was 25.0%. (The E/Z ratio was28/72.)

Example 29

To 66.0 g of the solution containing 4.39 g (15.0 mmol) of the hydrogenbromide salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and2.16 g (7.4 mmol) of the hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate obtained in Example 13 wasadded 5.1 g of water at −15 to −10° C., and the resulting mixture wasseparated into an aqueous and organic layer. To the aqueous layer wasadded 5.6 g (55.7 mmol) of a 36% hydrochloric acid at −10 to −5° C.,over a period of 30 minutes. After being held at that temperature for 2hours, the reaction mixture was filtered to give crystals. The crystalsobtained were washed with two portions of 10.9 g of acetone which hadbeen cooled to −10 to −5° C., and were dried in vacuo to give 2.69 g ofcrystals containing an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 2.42 g (9.74 mmol) in terms of hydrochloride. (The yieldwas 31.5% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.7/99.3.

Example 30

To 64.1 g of the solution containing 4.03 g (13.8 mmol) of the hydrogenbromide salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and3.32 g (7.9 mmol) of the hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate obtained in Example 14 wasadded 4.9 g of water at −15 to '10° C., and the resulting mixture wasseparated into an aqueous and organic layer. To the aqueous layer wasadded 5.5 g (53.9 mmol) of a 36% hydrochloric acid at −10 to −5° C. overa period of 30 minutes. After being held at that temperature for 2hours, the reaction mixture was filtered to give crystals. The crystalsobtained were washed with two portions of 10.6 g of acetone which hadbeen cooled to −10 to −5° C., and were dried in vacuous to give 2.57 gof crystals containing an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 2.24 g (8.99 mmol) in terms of hydrochloride. (The yieldwas 30.0% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.7/99.3.

Example 31

To 108.15 kg of the solution containing 8.68 kg (29.6 mol) of thehydrogen bromide salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and 4.36 kg (14.9 mol) of thehydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate obtained in Example 15 wasadded 8.30 kg of water at −18 to −16° C., and the resulting mixture wasseparated into an aqueous and organic layer. To the aqueous layer wasadded 8.88 kg (85.2 mol) of a 36% hydrochloric acid at −13 to −7° C.over a period of 2 hours. After being held at that temperature for 2hours, the reaction mixture was filtered to give crystals. The crystalsobtained were washed with four portions of 9.1 kg of acetone which hadbeen cooled to −10 to −5° C. to give 7.00 kg of crystals containing anacid salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 5.94 kg (23.9 mol) in terms of hydrochloride. (The yieldwas 47.3% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 kg in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.4/99.6.

Example 32

To 61.57 g of a solution containing 5.54 g (18.91 mmol) of the hydrogenbromide salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and2.18 g (7.44 mmol) of the hydrogen bromide salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate obtained in Example 16 wasadded 4.90 g of water at −20 to −15° C., and the resulting mixture wasseparated into an aqueous and organic layer. To the aqueous layer wasadded 3.53 g of acetone and then 5.58 g (53.60 mmol) of a 36%hydrochloric acid at −10 to −5° C. over a period of 0.5 hour. Afterbeing held at that temperature for 2 hours, the reaction mixture wasfiltered to give crystals. The crystals obtained were washed with twoportions of 10.52 g of acetone which had been cooled to −10 to −5° C. togive 4.22 g of crystals containing an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.83 g (15.41 mmol) in terms of hydrochloride. (The yieldwas 51.7 % based on methyl 2-propylidene-4-bromoacetoacetate.) Theamount of the acid salt of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in those crystalswas 0.015 g in terms of hydrochloride. The E/Z ratio of the acid salt ofmethyl 2-(2-aminothiazole-4-yl)-2-pentenoate was 0.4/99.6.

Production Example 2 of methyl 2-propylidene-4-bromoacetoacetate

Into a solution obtained by dissolving 8.14 g (136 mmol) of acetic acidin 81.6 g of methyl isobutyl ketone, three solutions of 58.5 g (300mmol) of methyl 4-bromoacetoacetate, 39.4 g (678 mmol) ofpropionaldehyde and 2.89 g (33.9 mmol) of piperidine in 3.50 g of methylisobutyl ketone were added dropwise in parallel (added simultaneously)over a period of 6 hours at −25 to −30° C. To the mixture which had beenheld at that temperature for three hours was added 170 g of methylisobutyl ketone, and the resultant reaction mixture was poured into 86.5g of a 1.4% aqueous hydrochloric acid. The mixture was heated to 5° C.and separated into an aqueous and organic layer. The organic layer waswashed with 45.1 g of aqueous sodium hydrogensulfite solution (4.5 g interms of sulfurous acid) at 0 to 5° C. The resultant oil layer wasfurther washed with 86.5 g of water to give 342 g of a solutioncontaining 61.6 g (262 mmol, 88% yield) of methyl2-propylidene-4-bromoacetoacetate in methyl isobutyl ketone. Thissolution was used directly in the next reaction without concentrating orthe like.

Example 33

To 39.6 g of a solution containing methyl2-propylidene-4-bromoacetoacetate in methyl isobutyl ketone obtained inProduction Example 2 (7.0 g, 30 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate), which had been cooled to −30° C.previously, a solution obtained by dissolving 2.5 g (33 mmol) ofthiourea in 10.4 g of N,N-dimethylformamide was poured quickly. Themixture was elevated in temperature and thereafter stirred at 20° C. for10 minutes. In 52.5 g of the resultant reaction mixture, 7.3 g of methyl2-(2-aminothiazole-4-yl)-2-pentenoate hydrobromide (E/Z ratio=33/67, 56%Z-isomer yield) was contained.

To 40.9 g of methyl ethyl ketone which had been cooled to −10° C., theforegoing reaction mixture was poured and cooled. To the resultingmixture was added 11.2 g (49 mmol) of 16% aqueous hydrochloric acid at−10 to −5° C. over a period of 30 minutes. After being held at thattemperature for 2 hours, the reaction mixture was filtered at the sametemperature to give crystals. The resulting crystals were washed with aportion of 10.5 g of methyl isobutyl ketone which had been cooled to −10to −5° C. and with two portions of 10.5 g of acetone which had beencooled to −10 to −5° C., and were dried in vacuo to afford 3.57 g ofcrystals containing an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.20 g (12.9 mmol) in terms of hydrochloride (The yield was43% based on methyl 2-propylidene-4-bromoacetoacetate). The amount ofthe acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.6/99.4.

Example 34

To 59.4 g of a solution containing methyl2-propylidene-4-bromoacetoacetate obtained in the same manner asProduction Example 2 (10.0 g, 43 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate) in methyl isobutyl ketone, which hadbeen cooled to −30° C. previously, a solution obtained by dissolving3.56 g (47 mmol) of thiourea in 14.7 g of N,N-dimethylformamide waspoured quickly. The mixture was elevated in temperature and thereafterstirred at 20° C. for 10 minutes. In 77.7 g of the resultant reactionmixture, 10.8 g of methyl 2-(2-aminothiazole-4-yl)-2-pentenoatehydrobromide (E/Z ratio=33/67, 59% Z-isomer yield) was contained.

To 38.8 g (77.6 mmol) of 7.3% aqueous hydrochloric acid, the foregoingreaction mixture was poured at −8 to 0° C. over a period of 2 minutes.After being held at −10 to −5° C. for 2 hours, the reaction mixture wasfiltered at that temperature to give crystals. The resulting crystalswere washed with a portion of 17 g of methyl isobutyl ketone cooled to−10 to −5° C. and with two portions of 15 g and 10 g of acetone cooledto −10 to −5° C., and were dried in vacuo to afford 5.58 g of crystalscontaining the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The composition of the resultant crystals was 4.16 g of the Z-isomer interms of free (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate (content incrystals: 74.6%, 19.6 mmol; yield based on2-propylidene-4-bromoacetoacetate: 46%) and 0.02 g of the E-isomer interms of free (E)-2-(2-aminothiazole-4-yl)-2-pentenoate (content incrystals: 0.44%, 0.11 mmol). (The E/Z ratio was 0.6/99.4.)

As acidic components 0.59 g of hydrogen chloride (content in crystals:10.5%, 16.2 mmol) and 0.47 g of hydrogen bromide (content in crystals:8.4%, 5.9 mmol) were contained in the crystals. The amount of moisturecontained in the crystals was 0.35 g (content in crystals: 6.2%, 19.5mmol).

The total content of the foregoing components in the crystals were 100%.

Example 35

To 59.4 g of a solution containing methyl2-propylidene-4-bromoacetoacetate obtained in the same manner asProduction Example 2 (10.0 g, 43 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate) in methyl isobutyl ketone, which hadbeen cooled to −30° C. previously, a solution obtained by dissolving3.56 g (47 mmol) of thiourea in 14.7 g of N,N-dimethylformamide waspoured quickly. The mixture was elevated in temperature and thereafterstirred at 0° C. for 5 minutes. To 38.8 g (77.6 mmol) of 7.3% aqueoushydrochloric acid, 77.7 g of the reaction mixture obtained above waspoured at −10 to −3° C. over a period of 2 minutes. After being held at0° C. for 1.5 hours, the reaction mixture was cooled to −10° C. over aperiod of 0.5 hour and held at −10° C. for 0.5 hour. The resultantreaction mixture was filtered at that temperature to give crystals. Theresulting crystals were washed with a portion of 15 g of methyl isobutylketone cooled to −10° C. and with two portions of 15 g of acetone cooledto −10° C., and were dried in vacuo to afford 5.50 g of crystalscontaining the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

In the crystals, there was 4.92 g (19.8 mmol) in terms of hydrochlorideof the acid salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.(The yield was 46% based on methyl 2-propylidene-4-bromoacetoacetate.)The content of the acid salt of(E)-2-(2-aminothiazole-4-yl)-2-pentenoate in the crystals was 0.01 g interms of hydrochloride. The E/Z ratio of the acid salt of2-(2-aminothiazole-4-yl)-2-pentenoate was 0.2/99.8.

Example 36

To 41.2 g of a solution containing methyl2-propylidene-4-bromoacetoacetate obtained in the same manner asProduction Example 2 (7.0 g, 30 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate) in methyl isobutyl ketone, which hadbeen cooled to −30° C. previously, a solution obtained by dissolving2.49 g (33 mmol) of thiourea in 10.3 g of N,N-dimethylformamide waspoured quickly. The mixture was elevated in temperature and thereafterstirred at 20° C. for 10 minutes. To 54.0 g of the reaction mixtureobtained, 12.5 g (54 mmol) of 15.8% aqueous hydrochloric acid was pouredat −10 to −5° C. over a period of 30 minutes. After being held at thattemperature for 2 hours, the resultant reaction mixture was filtered atthe same temperature to give crystals. The resulting crystals werewashed with two portions of 10.5 g of acetone cooled to −10° C., andwere dried in vacuo to afford 3.99 g of crystals containing the acidsalt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

In the crystals, there was 3.52 g (14.2 mmol) in terms of hydrochlorideof the acid salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.(The yield was 48% based on methyl 2-propylidene-4-bromoacetoacetate.)The content of the acid salt of(E)-2-(2-aminothiazole-4-yl)-2-pentenoate in the crystals was 0.02 g interms of hydrochloride. The E/Z ratio of the acid salt of2-(2-aminothiazole-4-yl)-2-pentenoate was 0.7/99.3.

Production Example 3 of methyl 2-propylidene-4-bromoacetoacetate

Into a solution obtained by dissolving 27.5 g (0.46 mmol) of acetic acidin 272 g of 1-chlorobutane, 195 g (1.00 mol) of methyl4-bromoacetoacetate, 133 g (2.29 mol) of propionaldehyde and 9.73 g(0.11 mmol) of piperidine, were added dropwise separately in parallelover a period of 6 hours at −25 to −30° C. After being held at thattemperature for 2 hours, the reaction mixture was poured into 292 g of a1.4% aqueous hydrochloric acid. The mixture was heated to 5° C. andseparated into an aqueous and organic layer. The organic layer waswashed with 358 g of an aqueous sodium hydrogensulfite solution (35.8 gin terms of sulfurous acid) at 0 to 5° C. and separated into two layers.The resultant oil layer was further washed with 292 g of water to give551 g of a solution containing 207 g (0.88 mol, 88% yield) of methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane. This solution wasused directly in the next reaction without being subjected toconcentration or the like.

Example 35

To 18.6 g of a solution containing methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained inProduction Example 3 (7.0 g, 30 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate), 9.8 g of 1-chlorobutane and 9.8 g ofacetone were added, and the mixture was cooled to −30° C. To theresulting mixture, a solution obtained by dissolving 2.5 g (33 mmol) ofthiourea in 10.3 g of N,N-dimethylformamide was poured quickly. Themixture was elevated in temperature and thereafter stirred at 20° C. for10 minutes. In the resultant reaction mixture, 7.8 g of methyl2-(2-aminothiazole-4-yl)-2-pentenoate hydrobromide (E/Z ratio=30/70, 63%Z-isomer yield) was contained.

To 9.1 g of 1-chlorobutane which had been cooled to −10° C., theforegoing reaction mixture was poured and cooled. To the resultingmixture was added 6.9 g of water and the mixture was separated into anaqueous and organic layer at −3° C. To the thus obtained aqueoussolution containing methyl 2-(2-aminothiazole-4-yl)-2-pentenoatehydrobromide was added 5.4 g (54 mmol) of a 36% aqueous hydrochloricacid at −10 to −5° C. over a period of 30 minutes. After being held atthat temperature for 2 hours, the reaction mixture was filtered at thesame temperature to give crystals. The resulting crystals were washedwith two portions of 10.5 g of acetone which had been cooled to −10 to−5° C., and were dried in vacuous to afford 3.83 g of crystalscontaining an acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.36 g (13.5 mmol) in terms of hydrochloride. (The yieldwas 45% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.03 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.9/99.1.

Example 38

In the same manner as Example 37 except for adding the aqueous solutioncontaining methyl 2-(2-aminothiazole-4-yl)-2-pentenoate hydrobromide to5.4 g of a 36% aqueous hydrochloric acid (54 mmol) at −10 to −5° C.,3.87 g of crystals containing the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate was obtained.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.44 g (13.8 mmol) in terms of hydrochloride. (The yieldwas 46% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.6/99.4.

Example 39

In the same manner as Example 37 except that about 3 mg of crystals ofmethyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate hydrochloride wasadded, and then 1.8 g of a 36% aqueous hydrochloric acid (18 mmol) wasadded to the aqueous solution containing methyl2-(2-aminothiazole-4-yl)-2-pentenoate hydrobromide at −10 to −5° C., andstirring at that temperature for 30 minutes to form crystals, andthereafter 3.6 g of a 36% aqueous hydrochloric acid (36 mmol) was addedat the same temperature over a period of 1 hour, 3.82 g of crystalscontaining the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate was obtained.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.37 g (13.5 mmol) in terms of hydrochloride. (The yieldwas 45% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.02 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 0.5/99.5.

Example 40

To 18.0 g of a solution containing methyl2-propylidene-4-bromoacetoacetate in 1-chlorobutane obtained in the samemanner as Production Example 3 (7.0 g, 30 mmol in terms of pure methyl2-propylidene-4-bromoacetoacetate), which had been cooled to −30° C., asolution obtained by dissolving 2.5 g (33 mmol) of thiourea in 10.3 g ofN,N-dimethylformamide was poured quickly. The mixture was elevated intemperature and thereafter stirred at 20° C. for 10 minutes. Theresultant reaction mixture was added to 27.2 g of a 7.3% aqueoushydrochloric acid (54 mmol) at −6 to −5° C. over a period of 5 minutesand held at −10 to −5° C. for 2 hours. The reaction mixture was filteredat that temperature to give crystals. The resulting crystals were washedwith two portions of 10.5 g of acetone which had been cooled to −10 to−5° C., and were dried in vacuo to afford 4.06 g of crystals containingan acid salt of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate.

The amount of the acid salt of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate contained in the crystalsobtained was 3.54 g (14.2 mmol) in terms of hydrochloride. (The yieldwas 48% based on methyl 2-propylidene-4-bromoacetoacetate.) The amountof the acid salt of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoatecontained in those crystals was 0.04 g in terms of hydrochloride. TheE/Z ratio of the acid salt of methyl2-(2-aminothiazole-4-yl)-2-pentenoate was 1.0/99.0.

Production Example 4 of methyl 2-propylidene-4-bromoacetoacetate

In 105.76 g of methyl isobutyl ketone, 75.01 g of methyl4-chloroacetoacetate, 43.41 g of propionaldehyde and 2.99 g of aceticacid were dissolved. After cooling the mixture to −30° C., a mixedsolution of 2.54 g of piperidine and 3.44 g of methyl isobutyl ketonewas added at −27±2° C. over a period of 30 minutes. After holding thereaction mixture at that temperature for 2 hours, 295.5 g of a 0.35%aqueous hydrochloric acid and 10.6 g of methyl isobutyl ketone wereadded to the mixture. The mixture was heated to 3° C. and separated intoan aqueous and organic layer. The organic layer was washed at 0 to 5° C.with 295.5 g of a 1% aqueous sodium hydrogencarbonate solution and 295.5g of water in this order to give 192.03 g of a solution of methyl2-propylidene-4-chloroacetoacetate.

To 191.68 g of this solution was added 203.49 g ofN,N-dimethylformamide, and the mixture was cooled to 10° C. To thismixture was added 122.80 g of sodium bromide, and the mixture was heatedto 22° C. and stirred vigorously for 3 hours. The resultant reactionsolution was cooled to 5° C., washed with 356 g of water, and thenseparated to give 202.27g of a solution of methyl2-propylidene-4-bromoacetoacetate in methyl isobutyl ketone (thesolution containing 80.83 g of methyl2-propylidene-4-bromoacetoacetate).

Example 41

To 8.11 g of the methyl 2-propylidene-4-bromoacetoacetate solution inmethyl isobutyl ketone obtained in Production Example 4 (3.24 g in termsof pure methyl 2-propylidene-4-bromoacetoacetate), a solution obtainedby dissolving 1.50 g of thiourea in 6.19 g of N,N-dimethylformamide wasadded quickly and stirred at 20° C. for 5 minutes. The foregoingreaction mixture was poured into a mixture of 29.15 g of a 2.7% aqueoussodium hydroxide solution and 7.95 g of methyl isobutyl ketone, themixture having been cooled to 0 to 5° C. previously, and 4.65 g ofmethyl isobutyl ketone was further added. The resultant mixture was thenseparated to give 22.5 g of an organic layer and 38.4 g of an aqueouslayer. The high-performance liquid chromatography analysis indicatedthat the organic layer contained 1.52 g of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and 0.68 g of methyl(E)-2-(2-aminothiazole-4-yl)-2-pentenoate and the aqueous layercontained 0.09 g of methyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate and0.09 g of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoate. The analysisalso indicated that the total yield of methyl(Z)-2-(2-aminothiazole-4-yl)-2-pentenoate in the organic and aqueouslayers was 56.4% and the E/Z ratio was 32.4/67.6.

Examples 42 to 52

The results shown in Table 3 were obtained by carrying out the reactionand the post-treatment in the same manner as Example 41 except that thereaction temperature and the reaction time were set to the valuesprovided in Table 3.

TABLE 3 Reaction Reaction time Z-isomer temperature (° C.) (minute)yield (%) E/Z ratio Example 42 30 1 57.6 34/66 Example 43 30 3 57.436/64 Example 44 30 5 55.7 38/62 Example 45 25 2 54.2 32/68 Example 4625 5 57.8 35/65 Example 47 25 10 56.6 38/62 Example 48 20 10 57.9 34/65Example 49 15 20 55.7 34/66 Example 50 10 30 57.7 33/67 Example 51 5 5057.4 33/67 Example 52 0 120 56.7 33/67

Comparative Example 1 to 4

The results shown in Table 4 were obtained by carrying out the reactionand the post-treatment in the same manner as Example 41 except that thereaction temperature and the reaction time were set to the valuesprovided in Table 4.

TABLE 4 Reaction Reaction time Z-isomer temperature (° C.) (minute) (%)E/Z ratio Comparative 0 20 38.7 28/72 Example 1 Comparative 5 10 41.327/73 Example 2 Comparative 20 60 37.6 43/57 Example 3 Comparative 30 4036.2 62/38 Example 4

Production Example 5 of methyl 2-propylidene-4-bromoacetoacetate

In 34 g of dichloromethane, 5.0 g of methyl 4-bromoacetoacetate purity:95.6% ), 2.23 g of propionaldehyde and 0.15 g of acetic acid weredissolved. After cooling the mixture to −30° C., a mixed solution of0.26 g of piperidine and 1.18 g of dichloromethane was added at −27±2°C. over a period of 30 minutes. After holding the reaction mixture atthat temperature for 3.5 hours, 15 g of a 0.7% aqueous hydrochloric acidwas added to the mixture. The resulting mixture was heated to 3° C. andseparated into an aqueous and organic layer. The organic layer waswashed at 0 to 5° C. with 15 g of a 1% aqueous sodium hydrogencarbonatesolution and 15 g of water in this order and concentrated in vacuous ata temperature not higher than 15° C. to give 8.57 g of a concentratedsolution of methyl 2-propylidene-4-bromoacetoacetate (the solutioncontaining 5.31 g of methyl 2-propylidene-4-bromoacetoacetate).

Example 53

To 8.57 g of the methyl 2-propylidene-4-bromoacetoacetate solution indichloromethane obtained in Production Example 5 (5.31 g in terms ofpure methyl 2-propylidene-4-bromoacetoacetate), 14.16 g ofN,N-dimethylformamide and 7.97 g of dichloromethane were added. To thismixture, a solution obtained by dissolving 1.87 g of thiourea in 10.49 gof N,N-dimethylformamide was added at one time and stirred at 15° C. for10 minutes. The foregoing reaction mixture was poured into a mixture of36.4 g of a 2.7% aqueous sodium hydroxide solution and 13.3 g ofdichloromethane, the mixture having been cooled to 0 to 5° C.previously, and then the resultant mixture was separated into an aqueousand organic layer. The resulting organic layer was washed with twoportions of 47.7 g of a 3% saline solution at 0 to 5° C. and the aqueouslayer was extracted with 13.3 g of dichloromethane. The organic layersobtained were combined and concentrated in vacuo at a temperature nothigher than 15° C. to give 6.85 g of a concentrated solution of methyl2-(2-aminothiazole-4-yl)-2-pentenoate. In this solution, 2.33 g ofmethyl (Z)-2-(2-aminothiazole-4-yl)-2-pentenoate (51.7% yield) and 1.10g of methyl (E)-2-(2-aminothiazole-4-yl)-2-pentenoate were contained.The E/Z ratio was 28/72.

What is claimed is:
 1. A process for producing crystals of an acid saltof a (Z)-2-aminothiazole compound of formula (I)

wherein R¹ and R² independently represent an alkyl group having 1 to 5carbon atoms, Y represents a halogen atom, —OSO₃H or —OPO(OH)₂, mindicates the valence number of an inorganic acid of the formula (III)and n indicates an integer of 1 or 2, which process comprises: reactingthiourea and a halogenated compound of formula (VI)

wherein R¹, R² and the wavy line have the same meaning as defined inclaim 1, and X represents a bromine atom or an iodine atom, to form aZ-isomer rich acid salt of a 2-aminothiazole compound of formula (II)

wherein R¹ and R² independently represent an alkyl group having 1 to 5carbon atoms, X represents a bromine atom or an iodine atom and the wavyline means that this compound is a mixture of the E- and Z-isomers,reacting the salt of formula (II) with an inorganic acid of formula(III) HY  (III) wherein Y represents a halogen atom, —OSO₃H, or—OPO(OH)₂ in the presence of a solvent, and crystallizing from solutionthe (Z)-2-aminothiazole compound of formula (I).
 2. The processaccording to claim 1, wherein the inorganic acid of formula (III) isemployed as an aqueous solution or as an anhydrous inorganic acidoptionally absorbed in an organic solvent.
 3. The process according toclaim 1, wherein the reaction of the thiourea with the halogenatedcompound of formula (VI) takes place at a reaction temperature of −10 to+45° C.
 4. The process according to claim 3, wherein a reaction time Rtof the reaction is defined by the inequality 60e ^((−0.15T)) ≦Rt≦180e^((−0.1T)), wherein “T” means a reaction temperature of the reaction. 5.The process according to claim 1, wherein Y in the inorganic acid offormula (III) is a chlorine atom.